Cancer is the second leading cause of death in the United States, exceeded only by heart disease. (Cancer Facts and Figures. 2004, American Cancer Society, Inc.) Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors.
Improving the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. One approach for cancer treatment is targeting the molecular chaperone proteins of mammalian cells.
Molecular chaperone proteins are critical in ensuring the appropriate folding, stability, and function of other proteins in the cellular environment. An increasing body of evidence implicates chaperones not only in homeostatic function but to be involved in disease pathology as well. In particular, HSP90, a heat shock protein, is essential for the stability of a broad spectrum of client proteins, many of which are frequently mutated, over-expressed or constitutively activated in tumor cells. Aberrations in these clients can induce self-sufficiency in growth signals as well as insensitivity to anti-growth signals, tissue invasion, and evasion of apoptosis, among other oncogenic effects.
Inhibition of HSP90 leads to depletion of these oncogenic clients through the ubiquitin proteasome pathway. Interestingly, inhibitors of the HSP90 display a putative higher affinity for the activated form of the complex present in cancer cells, versus the latent form present in normal cells. As such, HSP90 inhibitors have the potential to accumulate in tumors and selectively kill cancer cells as compared to normal cells, creating a unique therapeutic window for these compounds.
Several known inhibitors of HSP90 currently exist, including the natural products radicicol (RDC) and geldanamycin (GDA), and the geldanamycin derivatives 17-AAG and 17-DMAG. Affinity flash chromatography experiments along with co-crystal structures provided evidence that GDA and RDC inhibit HSP90 by binding to its N-terminal ATP binding site (Ref 1). Geldanamycin (GDA) provides anti-tumor activity in cells, however its hepatotoxicity proved problematic in clinical trials (Ref 1). In addition, GDA is poorly soluble in aqueous solution. These two issues led to the development of improved GDA derivatives. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) and 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) are currently undergoing clinical evaluation as anticancer agents. These molecules are also limited by low solubility, a complex formulation and modest potency, as well as potential liver toxicity issues as described in dogs.
A limited number of small molecule inhibitors have also been identified, including the Conforma purine-based inhibitor series (WO 2006105372, WO 2005028434, WO 2003037860), Kyowa Hakko radicicol amines (WO 2006051808, WO 2005063222, 20050007782005063222), and the Vernalis pyrazole series (WO 2004050087, WO 2003055860, WO 2004072051, WO 2004096212). Each of these is still pre-clinical, and the opportunity to identify a small molecule inhibitor of HSP90 continues to hold great therapeutic promise.
Some pyrazole compounds and isoxazole compounds were shown to be HSP90 inhibitors (see, e.g., WO2003055860, WO2004050087, JP2005225787, WO2006018082, JP2006306755 and WO2004072051). Moreover, HSP90 inhibitors also include compounds with other five member heterocyclic ring systems that are conformationally similar to the pyrazole ring or isoxazole ring (see, e.g., FR2005-1801 20050222, WO2005/000300, WO2006117669, WO2006087077, WO2006010594, WO2006 1011052, WO2006 055760, and US2007155809).
There is a need for the development of more HSP90 inhibitors for the treatment of cancer.
The references cited herein are not admitted to be prior art to the claimed invention.